The results of SYL116011 have demonstrated that this treatment reduces the symptoms related to the allergy in 50% to 80%.

The ARVO meeting has considered the poster presentation to be of scientific interest, contributing therefore to its release.

Around 30% of the worldwide population show allergic symptoms and between 40-80% of them have the symptoms in their eyes.

Madrid, 7th of May, 2018. Within the framework of the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO), that has been held from the 29th of April and up to today, the 3rd of May, in Honolulu (Hawaii), Sylentis, pharmaceutical company belonging to the PharmaMar Group, has presented preclinical results on RNAi therapy, and has shown how SYL116011 acts on seasonal ocular allergies (Posterboard number: 5567 – A0259)i.

The abstract gathers the results of SYL116011 that show that this treatment which is being researched for ocular allergies caused by pollen, reduces the symptoms related to this allergy, such as swelling and tearing in between 50% and 80%, being possibly considered as a new potential treatment for seasonal ocular allergies. SYL116011 is administered once a day and has fewer secondary effects than antihistamines that usually provoke itchy eyes and drowsiness, apart from having to be administered between 3 and 4 times a day .

This meeting that had the purpose of sharing the latest progress in research in the area of vision and contributes to progress in the knowledge of basic science and cutting-edge clinical research has considered this poster to be of scientific interest, contributing to its release.

According to Ana Isabel Jiménez, Director of R&D at Sylentis, “eye allergies are one of the most common illnesses that allergists and ophthalmologists come across. The problem is that a majority of the drugs that are available for the treatment of ocular allergies are focused on alleviating, from time to time, the symptoms.”

As Victoria González, PHD, Sylentis explained “this new therapy allows the number of administrations to be reduced to once daily without inducing systemic side effects, and it is expected to improve the quality of life for patients suffering from seasonal allergies.”

Around 30% of the world´s population show allergic symptoms and around 40%-80% of them show these symptoms in their eyesii. Allergic illnesses that affect the eyes constitute a heterogeneous group of illnesses and show a wide range of symptoms; reddening, itching, burning sensation, pain and even an intolerance to light (photophobia). However, ocular allergies can manifest themselves independently or in conjunction with other symptoms such as rhinitis or asthma .

Sylentis, expert in the research of new treatments for ophthalmological and inflammatory illnesses, is a company leader in RNAi technology and it is one of the few companies in Europe that apply this technology to the field of ophthalmology.

About RNA interference (RNAi)RNA interference (RNAi) is a natural cellular process that regulates the expression of certain genes, providing a role in innate defense and development in animals and plants. This process is used to specifically silence genetic transcripts that encode protein-causing diseases. The therapeutic application of targeted siRNAs is booming given the specificity of gene silencing for a particular protein in a given tissue and the lack of side effects. This new approach to drug discovery is a promising technology that is rapidly moving in the translational research space , .

About SylentisSylentis, a company of PharmaMar (MSE:PHM), is a biotechnology company fully owned that develops innovative therapies harnessing the technology of post-transcriptional gene silencing or RNA interference (RNAi). Sylentis has developed an approach to efficiently design RNAi-based therapeutics that can be used to silence numerous disease-causing genes. We currently have a robust therapeutic program in ophthalmology with two candidates under development in Phase II and III studies for glaucoma (bamosiran) and ocular pain (SYL1001) , respectively. Sylentis is also developing new products for the treatment of several eye diseases such as ocular allergies and retina diseases. To know more about us, please visit us at www.sylentis.com.

DisclaimerThis document is a press release, not a prospectus. This document does not constitute or form part of an offering or invitation to sell or a solicitation to purchase, offer or subscribe shares of the company. Moreover, no reliance should be placed upon this document for any investment decision or contract and it does not constitute a recommendation of any type with regard to the shares of the company.

Topical administration of siRNA could be a new therapeutic option for the treatment of degenerative illnesses of the retina that presents processes of neovascularization .

Madrid, 4th of May, 2018. Within the framework of the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO), that has been held from the 29th of April to the 3rd of May in Honolulu (Hawaii), Sylentis, pharmaceutical company belonging to the PharmaMar Group (MSE:PHM), has presented the preclinical results of a new molecule (SYL1801), indicated for the treatment of age associated macular degeneration and which is administered topically.

This meeting which is held annually has the purpose of sharing the latest development in the understanding of the cutting-edge clinical science. In this context, Sylentis has participated with the presentation of the abstract Topical administration of siRNA targeting NRARP as a new treatment for choroidal neovascularization (Posterboard Number: 2634 - A0139)i, in which SYL1801 is evaluated for its role upon NRARP, a protein that controls the formation of new blood cells in the retina, that presents processes of neovascularization, the growth of new blood vessels.

As Ana Isabel Jiménez, Director of R&D at Sylentis, said ”macular degeneration is the primary cause of loss of vision in people over 50 years of age . The current treatments involve intravitreal infections, so at Sylentis we are trying to develop products that are of a topical use for this illness, therefore, in addition to the treatment, we would also be improving the quality of life of our patients.”

Sylentis is a pioneer in RNAi research, and is one of the few in Europe that applies this technology to the field of ophthalmology. It also continues with its research on new therapies for ophthalmological and inflammatory illnesses.

About SylentisSylentis, a company of PharmaMar (MSE:PHM), is a biotechnology company fully owned that develops innovative therapies harnessing the technology of post-transcriptional gene silencing or RNA interference (RNAi). Sylentis has developed an approach to efficiently design RNAi-based therapeutics that can be used to silence numerous disease-causing genes. We currently have a robust therapeutic program in ophthalmology with two candidates under development in Phase II and III studies for glaucoma (bamosiran) and ocular pain (SYL1001) , respectively. Sylentis is also developing new products for the treatment of several eye diseases such as ocular allergies and retina diseases. To know more about us, please visit us at www.sylentis.com.

DisclaimerThis document is a press release, not a prospectus. This document does not constitute or form part of an offering or invitation to sell or a solicitation to purchase, offer or subscribe shares of the company. Moreover, no reliance should be placed upon this document for any investment decision or contract and it does not constitute a recommendation of any type with regard to the shares of the company.

The studies carried out with tivanisiran showed an improvement in the inflammatory ocular parameters, tear quality, and a reduction in ocular pain, that is associated with dry eye syndrome

Madrid, May 3rd, 2018. Sylentis, Pharmaceutical Company belonging to the PharmaMar Group, has presented results from the clinical studies carried out with tivanisiran for the treatment of dry eye syndrome and that has enabled the start-up of the Phase III “Helix” clinical trial. The presentation has taken place within the framework of the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO) that has been held from the 29th of April to the 3rd of May in Honolulu, Hawaii.

The purpose if this meeting is to share the latest breakthroughs in research in the area of ophthalmology, to contribute to the progress in basic science and also in cutting-edge clinical research. In this context, Sylentis has participated at this event presenting the pre-clinical and clinical results of various compounds that are being developed for the treatment of ocular disorders. Among these, the abstract “Tivanisiran a new treatment for Dry Eye Disease, that improved signs and symptoms in clinical trials” (Posterboard number: 925 - B0103) is highlighted, the compound improving the ocular inflammatory parameters, tear quality and a reduction in ocular pain associated with dry eye disease is also underlined1.

The novel mechanism of action of tivanisiran, based on genetic silencing through RNA interference (RNAi), is targeted at the treatment of the signs and symptoms of this pathology, making it a firm candidate for the treatment of dry eye disease.

According to Ana Isabel Jiménez, Director of R&D at Sylentis, “we trust in our technology, innovative in this field, and we hope that tivanisiran will soon become a real alternative for the treatment of millions of people that suffer dry eye disease around the world.”

In this respect, Jiménez points out that “this is a significant step forward in the development of innovative drugs in different therapeutic areas through a novel technology of genetic silencing based on the RNA.”

Sylentis is a pioneer in RNAi research, and is one of the few in Europe that applies this technology to the field of ophthalmology. It also continues with its research on new therapies for ophthalmological and inflammatory illnesses.

It must be empathized that this pathology affects more than 5 million in Spain, between 10% and 20% of the population, mostly women, and almost 100% of these being elderly , . In this context, the phase III “Helix” study is being carried out in more than 30 hospitals in Spain, Germany, Estonia, Portugal, Slovakia and Italy, in 300 patients to evaluate the efficacy of this compound in the treatment of the sign and symptoms of dry eye syndrome.

About tivanisiran (SYL1001)Tivanisiran is a drug based on RNAi that is administered as preservative-free eye drops; it selectively inhibits production of the transient receptor potential cation channel (TRPV1). These receptors are ion channels that mediate the transmission of ocular pain. Tivanisiran is a small synthetic double-stranded RNA oligonucleotide (siRNA) with a novel and highly selective mechanism of action. Non-clinical studies conducted by Sylentis with SYL1001 have demonstrated it has high ability to inhibit this specific target and block the perception of ocular pain in animals3.Tivanisiran is a product under development for the treatment of signs and symptoms related to dry eye syndrome and has the potential to be developed for other pathologies that cause ocular pain (corneal lesions, refractive surgery, etc.) , , .

About RNA interference (RNAi)RNA interference (RNAi) is a natural cellular process that regulates the expression of certain genes, providing a role in innate defense and development in animals and plants. This process is used to specifically silence genetic transcripts that encode protein-causing diseases. The therapeutic application of targeted siRNAs is booming given the specificity of gene silencing for a particular protein in a given tissue and the lack of side effects. This new approach to drug discovery is a promising technology that is rapidly moving in the translational research space , .

About dry eye syndromeDry eye syndrome is a multifactorial disease of the tear film and ocular surface that produces symptoms of ocular discomfort, eyesight disorders, and tear film instability with potential damage to the ocular surface. Dry eye syndrome is accompanied by such symptoms as ocular pain, itching, stinging, and irritation of the eye tissues. It is a characteristic disease of developed countries, associated with pollution, air conditioning, the use of contact lenses, refractive surgery and continued use of computers. Moreover, the amount and quality of tears decrease with age. Prevalence is between 10% and 20% among people aged 50 or over, and it is more frequent in womeni,ii.

Dry eye can be treated with cyclosporin drops or autologous serum, but there is as yet no specific product for chronic treatment of the ocular pain related to dry eye syndrome; oral analgesics or anaesthetics are used in general. However, the main treatment consists of artificial tears, in the form of drops, gel or creams. Preservative-free eye drops have generally been found to offer the best long-term response.

About SylentisSylentis, a company of PharmaMar (MSE:PHM), is a biotechnology company fully owned that develops innovative therapies harnessing the technology of post-transcriptional gene silencing or RNA interference (RNAi). Sylentis has developed an approach to efficiently design RNAi-based therapeutics that can be used to silence numerous disease-causing genes. We currently have a robust therapeutic program in ophthalmology with two candidates under development in Phase II and III studies for glaucoma (bamosiran) and ocular pain (SYL1001) , respectively. Sylentis is also developing new products for the treatment of several eye diseases such as ocular allergies and retina diseases. To know more about us, please visit us at www.sylentis.com.

DisclaimerThis document is a press release, not a prospectus. This document does not constitute or form part of an offering or invitation to sell or a solicitation to purchase, offer or subscribe shares of the company. Moreover, no reliance should be placed upon this document for any investment decision or contract and it does not constitute a recommendation of any type with regard to the shares of the company.

The Company presents the preclinical and clinical results from studies of three molecules for the treatment of dry eye syndrome, macular degeneration and eye allergies.

The presentation will take place in the framework of the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO). That will be held from the 29th of April to the 3rd of May in Honolulu, Hawaii.

Madrid, April 26th, 2018. Sylentis, Pharmaceutical Company belonging to PharmaMar Group will present new results on three ophthalmological compounds for the treatment of dry eye syndrome, macular degeneration associated to age, administered topically, and also for the treatment of eye allergies. The mentioned presentations will take place under the framework of the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO) that will be held from the 29th of April up to the 3rd of May in Honolulu, Hawaii.

It comprises of various sessions, to where approximately 11,000 researchers and ophthalmologists attend every year to share the latest research developments in the field of ophthalmology, and which will contribute to a progress in the knowledge of both basic science and cutting edge treatments.

According to Ana Isabel Jiménez, Director of R&D at Sylentis, “we are proud to present our results to the first rate audience that is attending this meeting. We trust in our technology to become a real alternative for the treatment of millions of people that suffer from these types of illnesses in the future.”

In fact, Jiménez highlights that “currently, the line of work where we have progressed fastest is in ophthalmology, for the treatment of illnesses such as dry eye syndrome, allergies and retinal diseases.”

Sylentis, expert in the research of new treatments for ophthalmological and inflammatory illnesses, is a company leader in RNAi technology and it is one of the few companies in Europe that apply this technology to the field of ophthalmology.

About SylentisSylentis, a company of PharmaMar (MSE:PHM), is a biotechnology company fully owned that develops innovative therapies harnessing the technology of post-transcriptional gene silencing or RNA interference (RNAi). Sylentis has developed an approach to efficiently design RNAi-based therapeutics that can be used to silence numerous disease-causing genes. We currently have a robust therapeutic program in ophthalmology with two candidates under development in Phase II and III studies for glaucoma (bamosiran) and ocular pain (SYL1001) , respectively. Sylentis is also developing new products for the treatment of several eye diseases such as ocular allergies and retina diseases. To know more about us, please visit us at www.sylentis.com.

DisclaimerThis document is a press release, not a prospectus. This document does not constitute or form part of an offering or invitation to sell or a solicitation to purchase, offer or subscribe shares of the company. Moreover, no reliance should be placed upon this document for any investment decision or contract and it does not constitute a recommendation of any type with regard to the shares of the company.

This new investigational treatment, based on RNA interference, reaches the retina when administered in eye drops. This feature is expected to positively affect patients’ quality of life by eluding the use of current standard treatments administered by intraocular injections.

Madrid, 25 September 2017. Sylentis presents, for the first time, positive data on the efficacy of SYL136001v10, a siRNA (small interference RNA) for the treatment of neovascular diseases of the retina such as Age-Related Macular Degeneration (AMD) and Diabetic Retinopathy (DR). SYL136001v10 reaches the retina when administered topically, demonstrating that the siRNA may be applied in eye drops changing the treatment paradigm for patients suffering these diseases. “Currently, patients are treated in a hospital setting where they receive anti-VEGFs by intraocular injection. This procedure is not only painful and uncomfortable for the patient but also entails increasing financial commitments for our national health system”, notes Covadonga Pañeda, R&D Manager at Sylentis, and principal author of the studies.

The data will be presented at the XIII Annual Meeting of the Oligonucleotide Therapeutics Society (OTS) taking place in Bourdeaux, France between the 24th and the 27th of September and where the latest advances in oligonucleotide therapeutics will be presented.

Sylentis has identified NRARP (NOTCH-regulated Ankyrin Repeat Protein) as a potential target for the treatment of angiogenic diseases of the retina. NRARP is a key regulator of the molecular pathways leading to vessel formation; as such, the consequences of modulating the expression of this gene with RNAi has been studied in animal models of retinal neovascularization.

The results of the efficacy studies have shown that reduction of NRARP in the retina using RNAi leads to regression of neovascular lesions and that the lesion reductions observed are equivalent to those observed in response to anti-VEGF treatment, current standard treatment administered by intraocular injection.

Sylentis studies at the XIII Annual Meeting of the Oligonucleotide Therapeutics Society:

About RNA interference (RNAi)RNA interference (RNAi) is a natural cellular process that regulates the expression of certain genes, providing a role in innate defense and development in animal and plants. This process is used to specifically silence genetic transcripts that encode protein-causing diseases. The therapeutic application of targeted siRNAs is booming given the specificity of gene silencing for a particular protein in a given tissue and the lack of side effects. This new approach to drug discovery is a promising technology that is rapidly moving in the translational research space[i],[ii].

About SylentisSylentis, a company of PharmaMar (MSE:PHM), is a biotechnology company fully owned that develops innovative therapies harnessing the technology of post-transcriptional gene silencing or RNA interference (RNAi). Sylentis has developed an approach to efficiently design RNAi-based therapeutics that can be used to silence numerous disease-causing genes. We currently have a robust therapeutic program in ophthalmology with two candidates under development in Phase II studies for glaucoma (bamosiran)[iii] and ocular pain (SYL1001)11. Sylentis is also developing new products for the treatment of several eye diseases such as ocular allergies and retina diseases. To know more about us, please visit us at www.sylentis.com.

DisclaimerThis document is a press release, not a prospectus. This document does not constitute or form part of an offering or invitation to sell or a solicitation to purchase, offer or subscribe shares of the company. Moreover, no reliance should be placed upon this document for any investment decision or contract and it does not constitute a recommendation of any type with regard to the shares of the company.

HELIX is a Phase III clinical trial started by Sylentis with the investigational new drug SYL1001, based on RNA interference technology (RNAi).

The Company has agreed with the U.S. Food and Drug Administration (FDA) on plans for the Phase III clinical program, which is designed to support the submission of a New Drug Application (NDA). The Company has received final, End-of-Phase II meeting minutes from the FDA.

Sylentis is a global leader in investigating use of RNAi for dry eye syndrome and it is one of the few in Europe to take this development to the field of ophthalmology.

Dry eye syndrome occurs when the eye does not produce tears properly, or when the tears are not of the correct consistency and evaporate too quickly[1]. Affects both the tear and/or the ocular surface and between 10% and 20% of the population in Spain suffer from this illness, especially the above 40´s[2],[3], women and also almost 100% of the elderly1.

Madrid, May, 30th, 2017. The pharmaceutical Company Sylentis (PharmaMar Group) has announced the start of the first Phase III study, HELIX, with the investigational new drug, SYL1001 for the indication of dry eye syndrome. The Company has agreed with the U.S. Food and Drug Administration (FDA) on plans for the Phase III clinical program, which is designed to support the submission of a New Drug Application (NDA). The Company has received final, End-of-Phase II meeting minutes from the FDA. SYL1001 is an advance in the development of innovative compounds in different therapeutic fields, through the novel technology of gene silencing, based on RNA interference (RNAi). In the HELIX study, more than 30 centers from 5 European countries, including Spain, will participate with the objective of evaluating the effect of the ophthalmological solution SYL1001 for improvements in the signs and symptoms of dry eye syndrome in about 300 patients an area in which few therapeutic options exist today. SYL1001 is a compound based on RNAi being administered in the form of eye drops that block the synthesis of a receptor implicated in the pathology of dry eye syndrome.

In Spain it is estimated that 1 in 5 people that visit the ophthalmologist do it for this reason. Patients with dry-eye syndrome suffer the chronic loss of lubrication and hydration on the ocular surface. More than 5 million people in Spain suffer from this condition –this is between 10% and 20% of the population-1,2, mainly women over 40 years of age. The risk of developing this disorder increases in 35% every decade thereafter2. Around the world, 344 million people suffer from this syndrome.

Dry eye syndrome is characteristic in people that live in developed countries and is caused by pollution, air conditioning, the use of contact lenses, refractive eye surgery or the continued use of computers. The most common symptoms of this pathology are burning, a constant itching, eye fatigue, dryness, blurred vision, the sensation of having a foreign body or eye pain[4], are some of the symptoms

As explained by Dr Ana Isabel Jimenez, COO and Director of R&D at Sylentis, “the RNA interference on which we are working, could improve the signs and symptoms for patients that suffer from this syndrome, given that this compound could reduce the inflammatory parameters of the eye´s surface, could improve the quality of the tear and could reduce the ocular pain associated with dry eye syndrome. We consider that our molecule SYL1001 could be a very effective and important therapeutic alternative for these patients”.

The Company is working on the investigation of new treatments for ophthalmological and inflammatory illnesses. “Up to today, the line of work in which we have more rapidly advanced in is in ophthalmology, for the treatment of illnesses such as dry eye syndrome, glaucoma, ocular allergies and illnesses of the retina”, added Dr Jimenez.

What is RNA interference?

RNA interference is an innovative technology that looks for a reduction in the anomalous production of protein, silencing the RNA Messenger. The RNAi provides a great step forward, as it provides a new mechanism of action to confront numerous pathologies[5]. Nowadays there are two marketed products based on this technology and there are several drugs in different phases of clinical development.

Pathologies, such as dry eye syndrome, are produced by an alteration in certain proteins. Through this technology, the production of proteins that take part in various pathologies could be decreased or very specifically controlled[6].

“This is very promising as a new treatment for eye illnesses because it permits confronting the illness with a novel mechanism of action. Moreover, in all the clinical studies in which we have participated, the efficacy of SYL1001 has been demonstrated in patients, along with a high tolerance and safety to the ocular surface”, explained Dr Jose Manuel Benítez del Castillo Sánchez, professor of ophthalmology and section head at the Clinical Hospital San Carlos’ ocular surface and inflammation unit in Madrid.

The compounds based on RNAi usually have a prolonged effect in comparison with traditional drugs. “This drug is particularly interesting in chronic diseases and areas in which patient compliance is a challenge because it may show an increased duration of effect”, said Dr Benitez del Castillo.

Spain leads the HELIX study

With the purpose of progressing in this field, Sylentis has begun the multicenter, random, controlled and double blind Phase III clinical trial in more than 30 hospitals in Spain, Germany, Estonia, Portugal and Italy. The trial, in which 300 patients are going to be enrolled, and begins with one Spanish patient, will evaluate the efficacy of the product patented by Sylentis, SYL1001, in the treatment of the signs and symptoms of dry eye disease[7].

“Nowadays that, with the knowledge obtained, we have an opportunity to develop therapies based on RNAi”, concluded Dr Benitez del Castillo. “The challenge now is to transform this powerful technology into marketable products”.

SYL1001 is a drug based on RNAi that is administered as preservative-free eye drops; it selectively inhibits production of the transient receptor potential cation channel (TRPV1). These receptors are ion channels that mediate the transmission of ocular pain. SYL1001 is a small synthetic double-stranded RNA oligonucleotide (siRNA) with a novel and highly selective mechanism of action. Non-clinical studies conducted by Sylentis with SYL1001 have demonstrated it has high ability to inhibit this specific target and block the perception of ocular pain in animals3.

SYL1001 is a product undergoing development for the signs and symptoms related to with dry eye syndrome, and has potential to be developed for other pathologies that cause ocular pain (corneal lesions, refractive surgery, etc.)6,[8],[9],[10].

About RNA interference (RNAi)

RNA interference (RNAi) is a natural cellular process that regulates the expression of certain genes, providing a role in innate defense and development in animal and plants. This process is used to specifically silence genetic transcripts that encode protein-causing diseases. The therapeutic application of targeted siRNAs is booming given the specificity of gene silencing for a particular protein in a given tissue and the lack of side effects. This new approach to drug discovery is a promising technology that is rapidly moving in the translational research space[11],[12].

About dry eye syndrome

Dry eye syndrome is a multifactorial disease of the tear film and ocular surface that produces symptoms of ocular discomfort, eyesight disorders, and tear film instability with potential damage to the ocular surface. Dry eye syndrome is accompanied by such symptoms as ocular pain, itching, stinging, and irritation of the eye tissues. It is a characteristic disease of developed countries, associated with pollution, air conditioning, the use of contact lenses, refractive surgery and continued use of computers. Moreover, the amount and quality of tears decrease with age. Prevalence is between 10% and 20% among people aged 50 or over, and it is more frequent in women1,2.

Dry eye can be treated with cyclosporin drops or autologous serum, but there is as yet no specific product for chronic treatment of the ocular pain related to dry eye syndrome; oral analgesics or anaesthetics are used in general. However, the main treatment consists of artificial tears, in the form of drops, gel or creams. Preservative-free eye drops have generally been found to offer the best long-term response.

About Sylentis

Sylentis, a company of PharmaMar (MSE:PHM), is a biotechnology company fully owned that develops innovative therapies harnessing the technology of post-transcriptional gene silencing or RNA interference (RNAi). Sylentis has developed an approach to efficiently design RNAi-based therapeutics that can be used to silence numerous disease-causing genes. We currently have a robust therapeutic program in ophthalmology with two candidates under development in Phase II studies for glaucoma (bamosiran)[13] and ocular pain (SYL1001)11. Sylentis is also developing new products for the treatment of several eye diseases such as ocular allergies and retina diseases. To know more about us, please visit us at www.sylentis.com.

Disclaimer

This document is a press release, not a prospectus. This document does not constitute or form part of an offering or invitation to sell or a solicitation to purchase, offer or subscribe shares of the company. Moreover, no reliance should be placed upon this document for any investment decision or contract and it does not constitute a recommendation of any type with regard to the shares of the company.

SYL1001 is a compound under investigation for the treatment of dry eye disease.

It is a product based on the novel technology RNA interference (RNAi), developed for the treatment of signs and symptoms of this illness.

At the Annual Congress of the Association for Research in Vision and Ophthalmology 2017, around 11,000 attendees will meet form the 7-11 of May in Baltimore, USA.

Madrid, May, 9th, 2017. In the framework of the Annual Congress of the Association for Research in Vision and Ophthalmology 2017 (ARVO), being held from the 7-11 of May in Baltimore (USA), Sylentis, a pharmaceutical company from the PharmaMar Group (MSE:PHM), presents new preclinical and clinical developments with its molecule SYL1001 for the treatment of dry eye disease. This is a product based on the novel technology RNA interference (RNAi), developed for the treatment of the signs and symptoms of this pathology.

This Congress will bring together more than 11,000 top eye and vision researchers and clinicians from around the world to explore cutting-edge basic and clinical science. “We are proud to be able to present our results to such a well prepared audience. We trust our technology, innovative in its field, and we hope that SYL1001 will soon be a real alternative for treating millions of people that suffer from dry eye disease around the world”, states Ana Isabel Jiménez, R&D Director of Sylentis.

Accordingly, Sylentis participates at this event with the presentation of data from various clinical and preclinical trials. On one hand, the stability results of SYL1001 in different commercial containers. The stability of the compound in various containers and conditions through time concludes that all the formats analyzed guarantee the integrity and specifications of the product.

On the other hand, Sylentis has presented the results of the study of this product in animal models, to evaluate its efficacy in the treatment of the symptoms and signs of dry eye disease. These patients have a deficit of mucine, a protein found in tears, a low density in the goblet cells and inflammation of the ocular surface. These studies have concluded that SYL1001, apart from reducing the feeling of ocular discomfort, it also improves the quality of the tear and reduces inflammation. In animal models, the statistical increase in the levels of mucine (MUC5A+) present on the eye´s surface has also been demonstrated, allowing for the formation of a tear film. In this same study, an increase in the density of goblet cell (those producing and secreting mucine) and also in tear secretion was observed. The inflammatory mediators of the eye surface also decreased after treatment.

Finally, the Company presents a third study that demonstrates the existing correlation between the preclinical and clinical results in the search for the optimum and most efficient dose. Both, in animal and human models, the concentration of 1.125% of SYL1001 was observed to be the most efficient, along with a very low incidence of adverse events.

About SYL1001SYL1001 is a drug based on RNAi that is administered as preservative-free eye drops; it selectively inhibits production of the TRPV1 receptor. These receptors are ion channels that mediate the transmission of ocular pain. SYL1001 is a small synthetic double-stranded RNA oligonucleotide (siRNA) with a novel and highly selective mechanism of action. Non-clinical studies conducted by Sylentis with SYL1001 have demonstrated it has high ability to inhibit this specific target and block the perception of ocular pain in animals .SYL1001 is a product undergoing development for the treatment or prevention of ocular pain related to with dry eye syndrome, and has potential to be developed for other pathologies that cause ocular pain (corneal lesions, refractive surgery, etc.).

About RNA interference (RNAi)RNA interference (RNAi) is a natural cellular process that regulates the expression of certain genes, providing a role in innate defense and development in animal and plants. This process is used to specifically silence genetic transcripts that encode protein-causing diseases. The therapeutic application of targeted siRNAs is booming given the specificity of gene silencing for a particular protein in a given tissue and the lack of side effects. This new approach to drug discovery is a promising technology that is rapidly moving in the translational research space.

About dry eye syndromeDry eye syndrome is a multifactorial disease of the tear film and ocular surface that produces symptoms of ocular discomfort, eyesight disorders, and tear film instability with potential damage to the ocular surface. Dry eye syndrome is accompanied by such symptoms as ocular pain, itching, stinging, and irritation of the eye tissues. It is a characteristic disease of developed countries, associated with pollution, air conditioning, the use of contact lenses, refractive surgery and continued use of computers. Moreover, the amount and quality of tears decrease with age. Prevalence is between 5% and 30% among people aged 50 or over, and it is more frequent in women.

Dry eye can be treated with cyclosporin drops or autologous serum, but there is as yet no specific product for chronic treatment of the ocular pain related to dry eye syndrome; oral analgaesics or anaesthetics are used in general. However, the main treatment consists of artificial tears, in the form of drops, gel or creams. Preservative-free eye drops have generally been found to offer the best long-term response.

About SylentisSylentis, a company of PharmaMar (MSE:PHM), is a biotechnology company fully owned that develops innovative therapies harnessing the technology of post-transcriptional gene silencing or RNA interference (RNAi). Sylentis has developed an approach to efficiently design RNAi-based therapeutics that can be used to silence numerous disease-causing genes. We currently have a robust therapeutic program in ophthalmology with two candidates under development in Phase II studies for glaucoma (bamosiran) and ocular pain (SYL1001)II,III,IV. Sylentis is also developing new products for the treatment of several eye diseases such as ocular allergies and retina diseases. To know more about us, please visit us at www.sylentis.com.

DisclaimerThis document is a press release, not a prospectus. This document does not constitute or form part of an offering or invitation to sell or a solicitation to purchase, offer or subscribe shares of the company. Moreover, no reliance should be placed upon this document for any investment decision or contract and it does not constitute a recommendation of any type with regard to the shares of the company.

Phase II dose-finding and efficacy trials (SYL1001_II and SYL1001_III) achieved their primary endpoints in terms of ocular pain (VAS) (p<0.016) and hyperaemia reduction with a dose of 1.125% (p<0.0134).

SYL1001 was well tolerated at all evaluated doses and the percentage of adverse events was similar to the placebo group.

The results and additional analysis will be presented at ARVO 2016 (The Association for Research in Vision and Ophthalmology).

Madrid, Monday 14th March 2016: Sylentis, a pharmaceutical company in the PharmaMar Group (MSE:PHM) and a pioneer in the research and development of new drugs based on gene silencing (interference RNA, RNAi), has presented the results of two Phase II dose-finding and efficacy assessment clinical trials (SYL1001_II and SYL1001_III) with the investigational medicinal product SYL1001 for treating ocular discomfort related to dry eye syndrome.

These randomised parallel group, double-masked and placebo controlled Phase II trials took place at 8 centres in two European countries: Spain and Estonia. A total of 127 patients with ocular pain related to dry eye syndrome took part in the trials, which assessed safety and efficacy of four doses of SYL1001 (0.375%, 0.75%, 1.125% and 2.25%) against placebo following 10 days of once-per-day administration in the form of eye drops.

The results revealed that 1.125% was an optimal dose which achieved the best primary and secondary endpoints, reducing not only ocular pain but also conjunctival hyperaemia related to dry eye syndrome.

The two trials also confirmed a favourable safety and tolerance profile of SYL1001, previously observed in Phase I trial, with no differences in the percentage of adverse events between the assessed doses of SYL1001 and placebo group.

"These positive results support continuing clinical development of SYL1001. Sylentis is currently designing the Phase III clinical program which it will be validated with the relevant regulatory authorities," said Dr Ana Isabel Jiménez, COO of Sylentis.

The results and additional analysis of these clinical trials will be presented at the ARVO conference in May 2016.

About the SYL1001_II (NCT01776658) and SYL1001_III (NCT02455999) trials

SYL1001_II/III are dose-finding, multi-centre randomised parallel-group double-masked placebo-controlled Phase II clinical trials to evaluate the efficacy and safety of SYL1001 in patients with ocular pain related to dry eye syndrome after ten days of treatment (one drop per day in each eye).

SYL1001_II included 61 patients at 5 centres in Spain, divided into three groups of 20 patients each, who received SYL1001 (1.125% or 2.25%) or placebo. SYL1001_III included 66 patients at 5 centres in Spain and Estonia, divided into three groups of approximately 22 patients each and treated with SYL1001 (0.375% or 0.75%) or placebo.

Secondary endpoints included assessment of vital signs, blood and urine analysis, and alteration of ocular parameters (IOP, TBUT, Schirmer test, visual acuity, and assessment of the anterior segment) together with the appearance of adverse events as a measure of tolerance.

About SYL1001

SYL1001 is a drug based on RNAi that is administered as preservative-free eye drops; it selectively inhibits production of the TRPV1 receptor. These receptors are ion channels that mediate the transmission of ocular pain. SYL1001 is a small synthetic double-stranded RNA oligonucleotide (siRNA) with a novel and highly selective mechanism of action. Non-clinical studies conducted by Sylentis with SYL1001 have demonstrated it has high ability to inhibit this specific target and block the perception of ocular pain in animals .

SYL1001 is a product undergoing development for the treatment or prevention of ocular pain related to with dry eye syndrome, and has potential to be developed for other pathologies that cause ocular pain (corneal lesions, refractive surgery, etc.)...

About RNA interference (RNAi)

RNA interference (RNAi) is a natural cellular process that regulates the expression of certain genes, providing a role in innate defense and development in animal and plants. This process is used to specifically silence genetic transcripts that encode protein-causing diseases. The therapeutic application of targeted siRNAs is booming given the specificity of gene silencing for a particular protein in a given tissue and the lack of side effects. This new approach to drug discovery is a promising technology that is rapidly moving in the translational research space .

About dry eye syndrome

Dry eye syndrome is a multifactorial disease of the tear film and ocular surface that produces symptoms of ocular discomfort, eyesight disorders, and tear film instability with potential damage to the ocular surface. Dry eye syndrome is accompanied by such symptoms as ocular pain, itching, stinging, and irritation of the eye tissues. It is a characteristic disease of developed countries, associated with pollution, air conditioning, the use of contact lenses, refractive surgery and continued use of computers. Moreover, the amount and quality of tears decrease with age. Prevalence is between 5% and 30% among people aged 50 or over, and it is more frequent in women .

Dry eye can be treated with cyclosporin drops or autologous serum, but there is as yet no specific product for chronic treatment of the ocular pain related to dry eye syndrome; oral analgaesics or anaesthetics are used in general. However, the main treatment consists of artificial tears, in the form of drops, gel or creams. Preservative-free eye drops have generally been found to offer the best long-term response.

About Sylentis

Sylentis, a company of PharmaMar (MSE:PHM), is a biotechnology company fully owned that develops innovative therapies harnessing the technology of post-transcriptional gene silencing or RNA interference (RNAi). Sylentis has developed an approach to efficiently design RNAi-based therapeutics that can be used to silence numerous disease-causing genes. We currently have a robust therapeutic program in ophthalmology with two candidates under development in Phase II studies for glaucoma (bamosiran) and ocular pain (SYL1001)II,III,IV. Sylentis is also developing new products for the treatment of several eye diseases such as ocular allergies and retina diseases. To know more about us, please visit us at www.sylentis.com.

Disclaimer

This document is a press release, not a prospectus. This document does not constitute or form part of an offering or invitation to sell or a solicitation to purchase, offer or subscribe shares of the company. Moreover, no reliance should be placed upon this document for any investment decision or contract and it does not constitute a recommendation of any type with regard to the shares of the company.

All bamosiran doses similarly reduced the intraocular pressure (IOP). In patients with a baseline IOP greater than or equal to 25 mm Hg, 1.125% bamosiran showed more efficacy

The trial did not meet the secondary objective of demonstrating non-inferiority compared to timolol in the total patient population; however, bamosiran at dose 1.125% ((450 micrograms) showed non-inferiority in patients with baseline IOP greater than or equal to 25 mm Hg

Bamosiran was very well-tolerated and treatment-related adverse events were more frequent in patients treated with timolol

Madrid, October 2nd, 2015: Sylentis, a pharmaceutical company of Grupo Zeltia (MSE: ZEL), pioneer in research and development of new RNA interference (RNAi)-based therapies announced today top-line results of a dose-finding Phase II study, SYLTAG, for the novel RNAi therapeutic bamosiran in patients with open-angle glaucoma or ocular hypertension. The SYLTAG study, which includes 184 patients with a baseline IOP greater than or equal to 23 mm Hg, evaluates the efficacy and safety of four doses 0,375% (150 micrograms); 0,75% (300 micrograms); 1,125% (450 micrograms) y 1,5% (600 micrograms) given once a day for 28 days. The comparator group received timolol (0.5%), given twice a day.

After 28 days of treatment, the four groups treated with bamosiran (0.375%, 0.75%, 1.125% y 1.5%) showed a similar reduction in the IOP. Bamosiran did not meet the secondary objective of demonstrating non-inferiority compared to timolol for any of the doses in the total patient population; however, at dose 1.125% (450 micrograms) it showed non-inferiority in patients with baseline IOP greater than or equal to 25 mm Hg and it was non-inferior compared to timolol in this patient group. The results showed excellent tolerability of bamosiran in all the treated groups with a very low hyperhemia (less than 8%).

“All the bamosiran doses investigated in this study have shown a similar reduction in IOP, so that the identification of a dose in the whole study population could not be achieved. This is a frequent outcome of dose-finding studies with RNAi-based drugs, where identifying the most effective dose is difficult,” pointed out Ana Isabel Jiménez, Ph.D., Executive Operations Director, Sylentis, who added that “the results we have obtained in this study along with the good ocular tolerability of bamosiran given once a day as a preservative-free eye drop, will allow us to continue working on this approach to develop a novel and effective product for the treatment of glaucoma or ocular hypertension.”

About the SYLTAG study (NCT02250612):

SYLTAG is a multicenter, international, dose-finding Phase II, double masked, randomized and controlled study that investigated the efficacy and safety of bamosiran by measuring the IOP during the day after 28 days of treatment (one drop per day in each eye) in patients with open-angle glaucoma or ocular hypertension compared to the active control, timolol given twice a day. The study has enrolled 180 patients from 21 centers across Europe and the US, which were distributed in 5 groups of about 36 patients each to receive four different doses of bamosiran (0.375%, 0.75%, 1.125% and 1.5%) or timolol (0.5%), respectively.The primary efficacy endpoint of the study was to determine the most effective drug dose to reduce IOP during the day, at day 14 and 28. The secondary endpoints included comparison of efficacy against timolol and quality of life measurements (using the Glaucoma Quality of Life questionnaire (GQL-15). The trial also studied the safety profile and tolerability of the treatments by means of measuring ocular discomfort, clinical ophthalmological values, systemic tolerability and adverse events.

About bamosiran (SYL040012)

The investigational drug bamosiran (SYL040012) is an RNAi-based therapy administered as eye drops that selectively blocks the production of the β2-adrenergic receptors, which are directly involved in the IOP[i] through the regulation of the production and drainage of the aqueous humour. Bamosiran is a small interfering double-stranded RNA (siRNA) that specifically functions through a novel and highly specific mechanism. In preclinical studies, bamosiran has shown to be superior compared to glaucoma drugs dorzolamide and Xalatan (latanoprost) at preventing an increase in IOP in a relevant disease model[ii].

About RNA interference (RNAi)

RNA interference (RNAi) is a natural cellular process that regulates the expression of certain genes, providing a role in innate defense and development in animal and plants. This process is used in biotechnology[iii] to specifically silence genetic transcripts that encode protein-causing diseases. The therapeutic application of targeted siRNAs[iv] is booming[v] given the specificity of gene silencing for a particular protein in a given tissue and the lack of side effects. This new approach to drug discovery is a promising technology that is rapidly moving in the translational research space

About open-angle glaucoma

Glaucoma is one of the leading causes of irreversible blindness worldwide, characterized by a progressive loss of sight owing to optic nerve damage, which is often associated with intraocular pressure[vi]. In 2020, it is estimated more than 80 million people worldwide will have glaucoma and at least 6–8 million individuals will become bilaterally blind[vii]. Primary open-angle glaucoma (POAG) is the most prevalent form of this disease, accounting for approximately two-thirds of all diagnosed cases of glaucoma. Although risk factors include a history of intraocular pressure and age, many patients with POAG have a genetic basis[viii]. Reducing the intraocular pressure in the eye to prevent progressive loss of vision remains the mainstay of glaucoma treatment; however, more specific and long-lasting approaches are needed to improve patient management and increase therapeutic efficacy. Novel glaucoma treatments using RNAi therapeutics may help overcome the challenges faced by patients regarding treatment compliance.

About Sylentis

Sylentis, a company of Grupo Zeltia (Madrid Stock Exchange: ZEL) is a biotechnology company fully owned that develops innovative therapies harnessing the technology of post-transcriptional gene silencing or RNA interference (RNAi). The Company uses its own innovative RNAi platform called SIRFINDER®,for the development of new therapies. The technology allows for the optimized search of siRNAs that specifically target a gene causing of particular disease. Sylentis has developed an approach to efficiently turn these siRNA fragments into RNAi-based therapeutics that can be used to silence numerous disease-causing genes. We currently have a robust therapeutic program in ophthalmology with two candidates under development in Phase II studies for glaucoma (bamosiran) and ocular pain (SYL1001). There are also other RNAi-based investigational drugs at the discovery and preclinical stage for ocular diseases, inflammatory diseases and disorders of the central nervous system (CNS). To know more about us, please visit us at www-sylentis.com.

Disclaimer

This document is a press release, not a prospectus. This document does not constitute or form part of an offering or invitation to sell or a solicitation to purchase, offer or subscribe shares of the company. Moreover, no reliance should be placed upon this document for any investment decision or contract and it does not constitute a recommendation of any type with regard to the shares of the company.

The main endpoint of the trial is to establish the most effective dose of bamosiran for reducing intraocular pressure after 28 days' treatment.

The Phase IIb trial with bamosiran will be conducted at 21 centres in Spain, Germany, Estonia and the United States, enrolling 180 patients.

Madrid, 17 July 2014: Grupo Zeltia (MC:ZEL) has announced today that Sylentis, a pioneer in the research and development of new drugs based on gene silencing through RNA interference (RNAi), has been authorised by the Estonian authorities to commence a Phase IIb trial with bamosiran (SYL040012) for the treatment of glaucoma and ocular hypertension. This is the first authorisation in the list of countries where the trial is to be conducted, and it enables patient enrolment to commence.

The trial, named SYLTAG, is a dose-finding parallel randomized, investigator-masked trial involving 4 groups receiving bamosiran and a fifth group receiving an active control (timolol). It will be conducted at 21 centres in Spain, Estonia, Germany and the United States and will recruit 180 patients.

The primary endpoint of this Phase IIb trial is to establish the most effective dose of bamosiran, administered once per day in the form of eye drops, in terms of its effect on intraocular pressure after 28 days of treatment.

Secondary endpoints include:

Secondary efficacy-related endpoints: Assessment of the effect of treatment in comparison with the control (timolol), and changes in the quality of life in patients treated with the two drugs.Secondary safety-related endpoints: evaluation of local tolerability (eye discomfort), visual acuity, biomicroscopy, pachymetry, ophthalmoscopy, systemic tolerability, and adverse side effects.

This trial is part of the development of bamosiran as a topical drug for the treatment of ocular hypertension and glaucoma. It will make it possible to ascertain the optimal dose with a view to progressing to Phase III trials.

About bamosiran (SYL040012)

In preclinical trials with bamosiran, the siRNAs administered topically to treat ocular hypertension associated with open-angle glaucoma have proven effective in vivo. Three clinical trials have been conducted with bamosiran to date: Phase I (tolerability and effect on healthy volunteers), Phase Ib (tolerability and effect on patients), and Phase IIa (dose-finding and comparison with placebo). The positive results obtained in previous trials led to the design of this trial, in which Sylentis plans to find the most effective dose and assess its effect and tolerability in comparison with one of the benchmark drugs on the market for the treatment of intraocular pressure.

About Sylentis

Sylentis, a biopharmaceutical company in Grupo Zeltia (MC: ZEL), is a pioneer in the research and development of new drugs based on gene silencing (RNA interference—RNAi). Founded in 2006 as a spin-off from Grupo Zeltia subsidiary GENÓMICA, S.A.U., Sylentis is a subsidiary of Grupo Zeltia and a key player in the search for new therapies based on interference RNA (RNAi). Its strategy is based on the efficient design of small fragments of RNAi (short interfering RNAs, siRNAs) with pharmaceutical potential by searching the most appropriate sequences using bioinformatics; once a disease's target gene has been identified, SYLENTIS develops a quick and economical solution for siRNAs to silence that gene.

About interference RNA (RNAi)

Interference RNA (RNAi) has arisen in recent years as a promising technology with therapeutic applications. Discovered in plants in the 1990s, RNAi consists of highly efficient selective and specific inhibition of gene expression (Fire et al., 1998). RNAi is mediated by small fragments of double-stranded RNA, consisting of 19-23 nucleotides, which promote degradation of mRNA, thus inhibiting synthesis of the proteins for which they code. As this mechanism is used naturally by cells to regulate gene expression in a way that is both non-toxic and highly effective, RNAi has great therapeutic potential.

About open-angle glaucoma

Primary open-angle glaucoma (POAG) is the most prevalent form of glaucoma, accounting for approximately two-thirds of all diagnosed cases of glaucoma. It is defined as a multifactorial optic neuropathy consisting of a loss of retinal ganglion cells and characteristic atrophy of the optical nerve leading to progressive, irreversible blindness. The risk factors of POAG include high intraocular pressure (IOP), a family history of the disease, and old age (Marquis and Whitson, 2005). Although the physiopathological mechanisms by which high pressure leads to neuron damage are not known, most current therapies include drugs or surgery which seek to reduce IOP to a level that safely prevents progressive loss of vision.